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EP1680154B1 - Selbstbetätigter applikator für eine mikroprojektionsanordnung - Google Patents

Selbstbetätigter applikator für eine mikroprojektionsanordnung Download PDF

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Publication number
EP1680154B1
EP1680154B1 EP04796104A EP04796104A EP1680154B1 EP 1680154 B1 EP1680154 B1 EP 1680154B1 EP 04796104 A EP04796104 A EP 04796104A EP 04796104 A EP04796104 A EP 04796104A EP 1680154 B1 EP1680154 B1 EP 1680154B1
Authority
EP
European Patent Office
Prior art keywords
piston
spring
cap
applicator
impact
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP04796104A
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English (en)
French (fr)
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EP1680154A2 (de
EP1680154A4 (de
Inventor
Joseph C. Trautman
Lorin Olson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alza Corp
Original Assignee
Alza Corp
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Filing date
Publication date
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Publication of EP1680154A2 publication Critical patent/EP1680154A2/de
Publication of EP1680154A4 publication Critical patent/EP1680154A4/de
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Publication of EP1680154B1 publication Critical patent/EP1680154B1/de
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Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/20—Surgical instruments, devices or methods for vaccinating or cleaning the skin previous to the vaccination
    • A61B17/205—Vaccinating by means of needles or other puncturing devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws or setting implements
    • A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
    • A61B17/92—Impactors or extractors, e.g. for removing intramedullary devices
    • A61B2017/922—Devices for impaction, impact element
    • A61B2017/924—Impact element driving means
    • A61B2017/925—Impact element driving means a spring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0038—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles

Definitions

  • the present invention relates to an apparatus for applying a penetrating member to the skin by impact, and more particularly, the invention relates to a self-setting, auto-trigging impact device to reproducibly penetrate the stratum corneum with a penetrating member, such as a microprotrusion array, for transdermal delivery or sampling of an agent.
  • a penetrating member such as a microprotrusion array
  • Active agents are most conventionally administered either orally or by injection. Unfortunately, many agents are completely ineffective or have radically reduced efficacy when orally administered since they either are not absorbed or are adversely affected before entering the bloodstream and thus do not possess the desired activity. Further, orally administered agents typically do not take effect as quickly as injected agents. On the other hand, the direct injection of the agent into the bloodstream, while assuring no modification of the agent during administration, is a difficult, inconvenient, painful and uncomfortable procedure which sometimes results in poor patient compliance.
  • transdermal delivery provides for a method of administering active agents that would otherwise need to be delivered via hypodermic injection or intravenous infusion.
  • Transdermal agent delivery offers improvements in both of these areas.
  • Transdermal delivery when compared to oral delivery, avoids the harsh environment of the digestive tract, bypasses gastrointestinal drug metabolism, reduces first-pass effects and avoids the possible deactivation by digestive and liver enzymes.
  • transdermal refers to delivery of an active agent (e.g., a therapeutic agent, such as a drug or an immunologically active agent, such as a vaccine) through the skin to the local tissue or systemic circulatory system without substantial cutting or penetration of the skin, such as cutting with a surgical knife or piercing the skin with a hypodermic needle.
  • an active agent e.g., a therapeutic agent, such as a drug or an immunologically active agent, such as a vaccine
  • Transdermal agent delivery systems generally rely on passive diffusion to administer the agent, while active transdermal agent delivery systems rely on an external energy source, including electricity (e.g., iontophoresis) and ultrasound (e.g., phonophoresis), to deliver the agent.
  • Passive transdermal agent delivery systems typically include an agent reservoir containing a high concentration of the agent. The reservoir is adapted to contact the skin, which enables the agent to diffuse through the skin and into the body tissues or bloodstream of a patient.
  • transdermal agent flux is dependent upon the condition of the skin, the size and physical/chemical properties of the agent molecule, and the concentration gradient across the skin. Because of the low permeability of the skin to many active agents, transdermal delivery has had limited applications. This low permeability is attributed primarily to the stratum corneum, the outermost skin layer, which consists of flat, dead cells filled with keratin fibers (i.e., keratinocytes) surrounded by lipid bilayers. This highly-ordered structure of the lipid bilayers confers a relatively impermeable character to the stratum corneum.
  • a permeation enhancer when applied to a body surface through which the agent is delivered, enhances the flux of the agent therethrough.
  • the efficacy of these methods in enhancing transdermal protein flux has, in several instances, been limited.
  • Electrotransport uses an electrical potential, which results in the application of electric current to aid in the transport of the agent through a body surface, such as skin.
  • scarifiers generally included a plurality oftines or needles that were applied to the skin to and scratch or make small cuts in the area of application.
  • the vaccine was applied either topically on the skin, such as disclosed in U.S. Patent No. 5,487,726 , or as a wetted liquid applied to the scarifier tines, such as disclosed in U.S. Patent Nos. 4,453,926 , 4,109,655 , and 3,136,314 .
  • a serious disadvantage in using a scarifier to deliver an agent is the difficulty in determining the transdermal agent flux and the resulting dosage delivered. Also, due to the elastic, deforming and resilient nature of skin to deflect and resist puncturing, the tiny piercing elements often do not uniformly penetrate the skin and/or are wiped free of a liquid coating of an agent upon skin penetration.
  • the punctures or slits made in the skin tend to close up after removal of the piercing elements from the stratum corneum.
  • the elastic nature of the skin acts to remove the active agent liquid coating that has been applied to the tiny piercing elements upon penetration of these elements into the skin.
  • the tiny slits formed by the piercing elements heal quickly after removal of the device, thus limiting the passage of the liquid agent solution through the passageways created by the piercing elements and in turn limiting the transdermal flux of such devices.
  • WO 96/37155 WO 96/37256 , WO 96/17648 , WO 97/03718 , WO 99/11937 , WO 98/00193 , WO 97/48440 , WO 97/48441 , WO 97/48442 , WO 98/00193 , WO 99/64580 , WO 98/28037 , WO 98/29298 , and WO 98/29365 .
  • the disclosed systems and apparatus employ piercing elements of various shapes, sizes and arrays to pierce the outermost layer (i.e., the stratum corneum) of the skin.
  • the piercing elements disclosed in these references generally extend perpendicularly from a thin, flat member, such as a pad or sheet.
  • the piercing elements in some of these devices are extremely small, some having a microprojection length of only about 25 - 400 microns and a micropojection thickness of only about 5-50 microns. These tiny piercing/cutting elements make correspondingly small microslits/microcuts in the stratum corneum for enhancing transdermal agent delivery therethrough.
  • the disclosed systems typically include a reservoir for holding the active agent and a delivery systems that is adapted to transfer the agent from the reservoir through the stratum corneum, such as by hollow tines of the device itseft.
  • a delivery systems that is adapted to transfer the agent from the reservoir through the stratum corneum, such as by hollow tines of the device itseft.
  • Illustrative is the device disclosed in PCT Pub. WO 93/17754 , which has a liquid agent reservoir.
  • microprojection arrays When microprojection arrays are used to improve delivery or sampling of agent through the skin, consistent, complete, and repeatable penetration is desired.
  • Manual application of a skin patch having microprojections protruding from its skin-contacting side, often results in significant variation in puncture depth across the length and width of the patch.
  • manual application results in large variations in puncture depth between applications due to the manner in which the user applies the array a microprojection array to the stratum corneum with an automatic device, which provides in a consistent and repeatable manner, stratum corneum piercing, not only over the length and width of the microprotrusion array, but also from application of one microprojection array to the next.
  • Some known spring loaded applicator devices for delivery of lancets for body fluid (e.g., blood) sampling am described in PCT Pub. No. WO 9 9/26539 and WO 97/42886 .
  • these devices are difficult to use because they require two-handed pre-setting of the applicator device prior to the application.
  • the known spring loaded lancet applicators require either two sections of the device to be pulled apart for pro-setting or require one part of the device to be pulled apart for pre-setting or require one part of the device to be twisted with respect to another part of the device for pre-setting. In both of these motions, a two-handed pre-setting operation is required. Many of the patients using these devices possess neither the strength, nor the manual dexterity to pre-set these known applicator devices.
  • a further spring loaded applicator which is adapted to apply a microprojection array.
  • the noted applicator includes a pre-setting mechanism that allows one-handed pre-setting of the applicator.
  • US-A-2002/0091357 forms the basis for the two-part form of claim 1 and describes a device for impacting a microprojection member against a stratum corneum of a patient and comprises a housing, a cap, a piston, an impact spring and a latching assembly.
  • a drawback of the applicator is thus that the applicator still requires a separate step of manually pre-setting the device prior to use. It would thus be desirable to provide an applicator that is eliminates the step of manually pre-setting the applicator prior to use.
  • the impact spring has an impact (or stored) energy in the range of approximately 0.005 - 0.5 Joules/cm 2 . More preferably, the impact spring 40 has a stored energy in the range of approximately 0.01- 0.3 joules/cm 2 .
  • the impact spring has an impact velocity in the range of approximately 0.5 - 20 meters(m)/sec, more preferably, in the range of approximately 1.0 -10 m/sec.
  • the piston has a surface area in range of approximately 0.1 - 20 cm 2 , more preferably, in the range of 1.0 -10 cm 2 .
  • the microprojection member includes at least one biologically active agent.
  • a transdermal delivery system for delivering a biologically active agent to a patient that comprises (i) a patch systems, the patch system including a gel pack containing an agent formulation and a microprojection member having top and bottom surfaces, a plurality of openings that extend through the microprojection member and a plurality of stratum corneum-piercing microprojections that project from the bottom surface of the microprojection member, the microprojection member being adapted to receive the gel pack whereby the agent formulation flows through the microprojection member openings, and a device according to claim 1, wherein the first end of the housing is adapted to receive the microprojection member.
  • the applicator includes a retainer adapted to engage the applicator housing proximate the second end, the retainer being further adapted to receive and position the microprojection member.
  • the agent formulation includes at least one biologically active agent.
  • the biologically active agent is selected from the group consisting of a leutinizing hormone releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menotropins (urofollitropin (FSH) and LH)), vasopressin, desmopressin, corticotropin (ACTH), ACTH analogs such as ACTH (1-24), calcitonin, parathyroid hormone (PTH), vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, interferon alpha, interferon beta, interferon gamma, erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), glucagon, growth hormone release hormone (GHRH
  • the biologically active agent is selected from the group consisting of antigens in the form of proteins, polysaccharides, oligosaccharides, lipoproteins, weakened or killed viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster, weakened or killed bacteria such as bordetella pertussis, clostridium tetani, corynebacterium diphtheriae, group A streptococcus, legionella pneumophila, neisseria meningitides, pseudomonas aeruginosa, streptococcus pneumoniae, treponema pallidum, and vibrio cholerae and mixtures thereof.
  • viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster
  • the agent formulation includes at least one additional pharmaceutical agent selected from the group consisting of pathway patency modulators and vasoconstrictors.
  • FIGURE 1 is a front cross-sectional view of one embodiment of the applicator illustrating an initial configuration or primary position with a patch retainer attached to the applicator, according to the invention
  • FIGURE 2 is a front cross-sectional view of the retainer illustrating a pre-set position, according to the invention
  • FIGURE 3 is a front cross-sectional view of the retainer illustrating a an activated position with the piston proximate a skin site, according to the invention
  • FIGURE 4 is a side cross-sectional view of the applicator in the primary position shown in FIGURE 1 ;
  • FIGURE 5 is a side cross-sectional view of the applicator in the pro-set position shown in FIGURE 2 ;
  • FIGURE 6 is a side cross-sectional view of the applicator in the activated position shown in FIGURE 3 ;
  • FIGURE 7 is a front cross-sectional view of a patch retainer that is adapted to cooperate with the applicator shown in FIGURES 1 through 6 , according to the invention;
  • FIGURE 8 is a perspective view of the patch retainer shown in FIGURE 7 ;
  • FIGURE 9 is a partial perspective view of one embodiment of a microprojection array.
  • transdermal means the delivery of an agent into and/or through the skin for local or systemic therapy.
  • transdermal flux means the rate of transdermal delivery.
  • biologically active agent refers to a composition of matter or mixture containing a drug which is pharmacologically effective when administered in a therapeutically effective amount.
  • active agents include, without limitation, leutinizing hormone releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menotropins (urofollitropin (FSH) and LH)), vasopressin, desmopressin, corticotrophin (ACTH), ACTH analogs such as ACTH (1-24), calcitonin, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, interferon alpha, interferon beta, interferon gamma, erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor
  • the noted biologically active agents can also be in various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or nonirritating, pharmacologically acceptable salts. Further, simple derivatives of the active agents (such as ethers, esters, amides, etc.), which are easily hydrolyzed at body pH, enzymes, etc., can be employed.
  • biologically active agent also refers to a composition of matter or mixture containing a "vaccine” or other immunologically active agent or an agent which is capable of triggering the production of an immunologically active agent, and which is directly or indirectly immunologically effective when administered in an immunologically effective amount.
  • vaccine refers to conventional and/or commercially available vaccines, including, but not limited to, flu vaccines, Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, chicken pox vaccine, small pox vaccine, hepatitis vaccine, pertussis vaccine, and diphtheria vaccine, recombinant protein vaccines, DNA vaccines and therapeutic cancer vaccines.
  • vaccine thus includes, without limitation, antigens in the form of proteins, polysaccharides, oligosaccharides, lipoproteins, weakened or killed viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster, weakened or killed bacteria such as bordetella pertussis, clostridium tetani, corynebacterium diphtheriae, group A streptococcus, legionella pneumophila, neisseria meningitides, pseudomonas aeruginosa, streptococcus pneumoniae, treponema pallidum, and vibrio cholerae and mixtures thereof.
  • viruses such as cytomegalovirus, hepatitis B virus, hepatitis C virus, human papillomavirus, rubella virus, and varicella zoster
  • biologically effective amount or “biologically effective rate” shall be used when the biologically active agent is a pharmaceutically active agent and refers to the amount or rate of the pharmacologically active agent needed to effect the desired therapeutic, often beneficial, result.
  • biologically effective amount or “biologically effective rate” shall also be used when the biologically active agent is an immunologically active agent and refers to the amount or rate of the immunologically active agent needed to stimulate or initiate the desired immunologic, often beneficial result.
  • vasoconstrictors refers to a composition of matter or mixture that narrows the lumen of blood vessels and, hence, reduces peripheral blood flow.
  • suitable vasoconstrictors include, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, orinpressin, oxymetazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline and the mixtures thereof.
  • microprojections and “microprotrusions”, as used herein, refer to piercing elements that are adapted to pierce or cut through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a mammal and more particularly a human.
  • the microprojections have a projection length less than 1000 microns. In a further embodiment, the microprojections have a projection length of less than 500 microns, more preferably, less than 250 microns.
  • the microprojections typically have a width and thickness of about 5 to 50 microns.
  • the microprojections may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof.
  • microprojection array refers to a plurality of microprojections arranged in an array for piercing the stratum corneum.
  • the microprojection array may be formed by etching or punching a plurality of microprojections from a thin sheet and folding or bending the microprojections out of the plane of the sheet to form a configuration, such as that shown in Fig. 5 .
  • the microprojection array may also be formed in other known manners, such as by forming one or more strips having microprojections along an edge of each of the strip(s) as disclosed in U.S. Patent No. 6,050,988 .
  • references to the area of the sheet or member and reference to some property per area of the sheet or member are referring to the area bounded by the outer circumference or border of the sheet.
  • the applicator of the present invention can be readily employed for repeatable impact application of an array of microprojections to the stratum corneum in conjunction with transdermal therapeutic agent delivery or sampling.
  • the applicator 10 is described for use with a certain type of microprojection array, it should be understood that the applicator can also be used with other types of stratum corneum micro-penetrating members.
  • the applicator of the invention is auto pre-setting and thus eliminates the step of manually pre-setting the applicator prior to use.
  • the applicator is also auto-triggering.
  • the applicator can thus be readily used by patients having neither the hand strength, nor the manual dexterity to pre-set other types of spring-loaded applicator devices.
  • the applicator of the invention additionally employs a triggering mechanism that is loaded outside of the diameter of the impact spring that biases the piston away from the device, allowing the use of smaller diameter springs made from smaller diameter wire, which can store equal or greater energy with the same travel while weighing less.
  • the reduced mass of the impact spring also permits a lower force to be used to compress the spring in order to achieve greater impact velocity.
  • the impact spring and the pre-setting spring have different inner and outer diameters and their positions in the applicator prevent the possibility of accidentally placing a spring in the wrong location.
  • the piston, inner cup and outer cup can also be keyed so they can only be assembled in a functional orientation.
  • the piston, inner cup and outer cup are also designed and configured to snap together to avoid the need for additional assembly steps, such as inserting screws, ultrasonic welding, adhesive bonding or solvent bonding.
  • the snaps also make disassembly of the applicator difficult, discouraging anyone from tampering with the mechanism.
  • the applicator 10 generally includes a housing 12, having an inner cup 14, and a piston 30 movable within the housing 12. As illustrated in Fig. 1 , the housing 12 further includes an outer cup (or cap) 20 for actuating the applicator 10 to impact the stratum corneum with a patch 60 or microprojection array 64.
  • the applicator 10 further includes an impact spring 40 that is positioned inside the spring guide 22 that extends inwardly from the top 23 of the outer cup 20.
  • the impact spring 40 is also seated in the piston spring seat or recess 34. According to the invention, the impact spring 40 biases the piston 30 downward (in the direction denoted by arrow A) with respect to the applicator housing 12.
  • the piston 30 has a lower surface or face 32, which, according to the invention, can be substantially planar, slightly convex or configured to a body surface (i.e., a specific skin site).
  • a body surface i.e., a specific skin site.
  • the lower surface 32 of the piston 30 causes a microprojection array or a transdermal patch containing a microprojection array to impact and pierce the stratum corneum.
  • the piston face 32 preferably has a surface area in the range of approximately 0.1 - 20 cm 2 . More preferably, the piston face 32 has a surface area in the range of approximately 1-10 cm 2 .
  • the applicator 10 additionally includes a pre-setting spring 42 that is positioned around the impact spring.
  • the pre-setting spring 42 is also seated in the spring seat 16 disposed proximate the top of the inner cup 14. As discussed in detail herein, the pre-setting spring 42 biases the outer cup 20 upward (in the direction denoted by arrow B) with respect to the inner cup 14 after actuation of the applicator 10.
  • the inner cup 14 further includes a piston stop 18, having a top 19a and bottom 19b surface that maintains the piston 30 in a pre-set position and restricts motion of the piston 30 there beyond in an upward direction.
  • the piston 30 includes at least one, more preferably, at least two, locking members 36 (i.e., first latching assembly) that are disposed proximate the end opposite the piston face 32.
  • the locking members 36 are adapted to contact the outer cup 20 locking member seat 24 after actuation of the applicator 10 (see Fig. 6 ) and raise the piston 30 to pre-set position, as illustrated in Fig. 4 .
  • the piston 30 further includes at least one, more preferably, at least two, flexible release catches 38 (i.e., second latching assembly).
  • the release catches 38 are designed and adapted to communicate with (or be positioned on) the top 19a of the inner cup 14 piston stop 18. (see Figs. 1 and 2 ).
  • the release catches 38 are further adapted to flex inwardly and, hence, disengage from the stop 18 when the cup 20 and, hence, spring guide 22 moves from the primary position to the pre-set position (see Fig. 2 ).
  • Figs. 1- 6 further illustrate a patch retainer 50 operatively secured to the applicator 10.
  • the retainer 50 preferably has a substantially annular shape with a first end 52 that is configured to engage the leading end 15 of the inner cup 14.
  • the second or leading end 54 of the retainer 50 provides a stratum corneum contacting surface.
  • the retainer 50 includes a patch seat 56 that is adapted to receive the patch 60.
  • the manner in which the patch 60 is mounted in the retainer 50 can vary (for example, the patch 60 may be positioned proximate the leading end 54 of the retainer 50), it is preferred that the patch 60 is mounted distal from the leading end 54, as illustrated in Fig. 8 , in order to avoid inadvertent contact of the patch microprojections with other objects (e.g., the fingers of the user).
  • the patch 60 is connected by frangible sections of patch base material to an annular ring of patch material 62, which is adhered to the patch seat 56.
  • the patch 60 is separated from the retainer seat 56 by the downward force of the piston 30.
  • patch 60 may be releasably attached to the piston 30 or positioned on the skin beneath the piston 30.
  • the diameter of the wire, d should be maximized and the mean diameter of the spring should be minimized.
  • the impact spring 40 has a stored or impact energy in the range of approximately 0.005 - 0.5 joules/cm 2 , wherein the area (i.e., cm 2 ) refers to the piston face 32. More preferably, the impact spring 40 has a stored energy in the range of approximately 0.01- 0.3 joules/cm 2 .
  • the impact spring 40 has an impact velocity in the range of 0.5 - 20 m/sec. More preferably, the impact spring 40 has a velocity in the range of 1 - 10 m/sec.
  • Figs. 1 and 4 there is shown the applicator 10 in a primary or ready position with the patch 60 positioned in the retainer 50. As illustrated in Fig. 1 , in the primary position, the piston 30 is positioned against the piston stop 18 and the flexible release catches 38 are seated on the top 19a of the piston stop 18.
  • Fig. 2 and Fig. 4 which is a further cross-sectional view of the applicator 10 rotated approximately 90° with respect to the view shown in Fig. 2
  • the impact 40 and pre-setting 42 springs compress (i.e., energize) until the spring guide 22 contacts the release catches 38, flexing the release catches 38 inward (in the direction denoted by arrow R 1 and R 2 ) whereby the release catches 38 disengage from the piston stop 18 and the piston 30 moves downward to an activated position and impacts the skin site 5 (i.e., stratum corneum) with the patch 60 (see Figs. 3 and 6 ).
  • the force exerted on the cap 20 and, hence, skin site 5 i.e., hold-down force
  • the hold-down force is preferably less than 6.8 kg (15 lbs)
  • the hold-down force is in the range of approximately 0.91-6.8kg (2-15 lbs.)
  • the hold-down force is in the range of approximately 2.3-4.5 kg (5 - 10 lbs), which substantially reduces and, in most instances, eliminates re-coil of the applicator 10.
  • the hold-down force causes the stratum corneum to be stretched by the leading end 54 of the retainer 50 so that the skin site 5 is under optimal tension at the time the patch 60 impacts the skin site 5.
  • the retainer 50 includes a flexible biasing ring that is disposed on the leading end 54 of the retainer 50 that further stretches the stratum corneum when the releasing force is applied to the applicator 10.
  • the pre-setting spring 42 when the piston 30 is in the activated position (wherein the piston 30 is proximate the leading end 54 of the retainer 50), the pre-setting spring 42 is compressed (or energized) and, hence, biases the applicator outer cup 20 in an upward direction.
  • the biasing force provided by the pre-setting spring 42 moves the outer cup 20 and piston 30, which is in communication therewith (see Fig. 6 ), back to the primary position illustrated in Figs.1 and 6 when the downward force is removed from the outer cup 20.
  • the release catches 38 have a sloping face that communicates with the top 19a of the piston stop 18. According to this embodiment, when a user places the applicator against a skin site 5 and exerts a downward force, the impact 40 and pro-setting 42 springs compress and energize until a releasing force is achieved, whereby the release catches 38 disengage (i.e., slide off the piston stop 18) and the piston 30 moves downward to the activated position shown in Figs. 3 and 6 .
  • the applicator 10 of the invention can be used with a patch 60 that genetally includes a microprojection array 64, an agent reservoir, and a backing.
  • the applicator 10 can also be used with a microprojection array without an agent reservoir.
  • the microprojection array is used as a pretreatment member, which is followed by the application of an agent with a separate transdermal agent delivery or sampling device, such as disclosed in Co-Pending U.S. Application No. 60/514,387 .
  • the microprojection array may incorporate the agent as a coating on the microprojections, e.g., for delivering a vaccine intradermally, such as disclosed in U.S. Application Nos.10/674,626 and 60/514,433 .
  • the applicator 10 can also be used for impacting other micro-piercing elements against the stratum corneum, for example those disclosed in U.S. Pat. No. 5,879,326 and PCT Pub. WO 99/29364 .
  • the microprojection array 64 includes a plurality of microprojections 68 that extend downward from one surface of a sheet or plate 70.
  • the microprojections 68 are preferably sized and shaped to penetrate the stratum corneum of the epidermis when pressure is applied to the array 64 (or patch 60).
  • the microprojections 68 are further adapted to form microslits in a body surface to increase the administration of a substance (e.g., hydrogel formulation) through the body surface.
  • body surface refers generally to the skin of an animal or human.
  • the microprojections 68 are generally formed from a single piece of sheet material and are sufficiently sharp and long to puncture the stratum corneum of the skin.
  • the sheet 70 is formed with an opening 69 between the microprojections 68 to enhance the movement of the active agent therethrough.
  • microprojection array 64 described above and other microprojection devices and arrays that can be employed within the scope of the invention are disclosed in U.S. Pat. Nos. 6,322,808 , 6,230,051 B1 and Co-Pending U.S. Application No. 10/045,842 .
  • the applicator of the present invention can be used in connection with transdermal agent delivery, transdermal analyte (e.g., glucose) sampling, or both.
  • Transdermal delivery devices for use with the present invention include, but are not limited to, passive devices, negative pressure driven devices, osmotic devices, and reverse electrotransport devices.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
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Claims (17)

  1. Ein Gerät (10) zum Pressen eines Mikroprojektionselements (64) gegen die Hornschicht eines Patienten, umfassend:
    ein Gehäuse (12), welches ein erstes und ein zweites Ende besitzt, wobei das erste genannte Ende des Gehäuses angepasst wird, um die genannten Mikroprojektionselemente aufzunehmen;
    eine Abdeckung (10), welche angepasst wird, um von einer ursprünglichen Position in eine voreingestellte Position des besagten Gehäuses bewegt zu werden;
    ein Stempel (30) verschiebbar angeordnet innerhalb des besagten Gehäuses (12) zum Pressen des besagten Mikroprojektionselements (64) gegen die Hornschicht, wobei der besagte Stempel (30) angepasst wird, um von einer voreingestellten Position zu einer aktivierten Position zu wechseln;
    eine Stoßfeder (40) in Verbindung mit der besagten Abdeckung (20) und besagtem Stempel (30), wobei die besagte Stoßfeder (40) angepasst wird, um eine Schlagkraft gegen den Stempel (30) zu bieten und Ausrichtung des besagten Stempels (30) außerhalb des besagten ersten Endes des besagten Gehäuses (12) in Richtung der aktivierten Position nahe der Hornschicht, wobei die besagte Stoßfeder (40) angezogen ist, wenn die besagte Abdeckung (20) und der besagte Stempel (30) in der besagten voreingestellten Position, die für das besagte Gerät (10) kennzeichnend ist und Folgendes umfasst:
    eine Voreinstellungsfeder (42) in Verbindung mit der besagten Abdeckung (20) und dem besagten Gehäuse (12), wobei die besagte Voreinstellungsfeder (42) angepasst wird, um eine Voreinstellungskraft zu der besagten Abdeckung zu bieten (20) und außerhalb der besagten Abdeckung (20) von der besagten voreingestellten Position zur besagten Primärposition zu gelangen, wobei die besagte Voreinstellungsfeder (42) angezogen wird, wenn sich der besagte Stempel (30) in der genannten aktivierten Position befindet;
    ein erste Verriegelungsmontage (36) in Verbindung mit der genannten Abdeckung (20) und dem genannten Stempel (30), wobei die genannte Verriegelungsmontage (36) angepasst wird, um mit der besagten Abdeckung (20) und der besagter Voreinstellungsfeder (42) zu kooperieren, um den besagten Stempel (30) zu der besagten ursprünglichen Position zurückzuführen, nachdem die besagte Abdeckung (20) von der besagten voreingestellten Position zur ursprünglichen Position verschoben worden ist;
    eine zweite Verriegelungsmontage (38) in Verbindung mit besagtem Gehäuse (12) und besagtem Stempel (30) zur Positionierung des besagten Stempels in der genannten voreingestellten Position; und
    ein Auslösungselement in Verbindung mit besagter Abdeckung (20), wobei das besagte Auslösungselement angepasst wird, um mit der zweiten Verriegelungsmontage (38) zu kommunizieren, wenn die besagte Abdeckung (20) von der ursprünglichen Position bewegt wird, wobei die besagte Stoßfeder (40) aufgezogen wird und die besagte zweite Verriegelungsmontage (38) sich löst, wobei sich der besagte Stempel (30) von der besagten voreingestellten Position zur besagten aktivierten Position hinbewegt und das besagte Mikroprojektionselement (64) in die Hornschicht eindrückt.
  2. Das Gerät (10) nach Anspruch 1, wobei die besagte Stoßfeder (40) Energie im Bereich von ungefähr 0.005-0.5 Joules/cm2 gespeichert hat.
  3. Das Gerät (10) nach Anspruch 2, wobei die besagte Stoßfeder (40) Energie im Bereich von ungefähr 0.01-0.3 Joules/cm2 gespeichert hat.
  4. Das Gerät (10) nach Anspruch 1, wobei die besagte Stoßfeder (40) eine Aufprallgeschwindigkeit im Bereich von ungefähr 0.5-20 m/sec aufweist.
  5. Das Gerät (10) nach Anspruch 4, wobei die besagte Stoßfeder (40) eine Aufprallgeschwindigkeit im Bereich von ungefähr 1.0-10 m/sec aufweist.
  6. Das Gerät (10) nach Anspruch 1, wobei der besagte Stempel (30) eine Vorderseite beinhaltet (32) und die besagte Vorderseite (32) eine Fläche im Bereich von ungefähr 0.1-20 cm2 besitzt.
  7. Das Gerät (10) nach Anspruch 6, wobei die besagte Vorderseite (32) eine Fläche im Bereich von ungefähr 1.0-10 cm2 besitzt.
  8. Das Gerät (10) nach Anspruch 1, wobei das besagte Mikroprojektionselement (64) eine Organerfassung beinhaltet, welche mindestens einen biologischen aktiven Agenten aufweisen kann.
  9. Das Gerät (10) nach Anspruch 1, wobei die besagte Verriegelungsmontage (38) außerhalb der besagten Stoßfeder (40) angeordnet ist.
  10. Das Gerät nach Anspruch 1, wobei die besagte Voreinstellungsfeder (42) außerhalb der besagten Stoßfeder (40) angeordnet ist.
  11. Das Gerät nach Anspruch 1, dadurch gekennzeichnet, dass eine Halterung (50) angepasst wird, um das besagte Gehäuse (12) nahe des zweiten Endes einzurasten und dass die besagte Halterung (50) angepasst wird, um das besagte Mikroprojektionselement (64) aufzunehmen und zu positionieren.
  12. Ein transdermales Lieferungssystem zur Bereitstellung eines biologisch aktiven Agenten an einen Patienten, umfassend:
    ein Patchsystem, wobei besagtes Patchsystem ein Gelpack beinhaltet, welches aus einer Hydrogelrezeptur und einem Mikroprojektionselement (64) besteht, das eine obere und untere Oberfläche und eine Mehrzahl an Öffnungen aufweist, welche sich durch das besagte Mikroprojektionselement (64) erstrecken und eine Mehrzahl von Hornschichten-schneidenden Mikroprojektionen (68), welche sich von der besagten unteren Oberfläche zum besagten Mikroprojektionselement (64) projizieren, wobei das besagte Mikroprojektionselement (64) angepasst wird, um das Gelpack zu empfangen, wobei die besagte Hydrogelrezeptur durch die besagten Öffnungen der Mikroprojektionselemente (64) läuft; und
    ein Gerät (10) gemäß Anspruch 1, wobei das besagte erste Ende des besagten Gehäuses (12) angepasst wird, um die besagten Mikroprojektionselemente (64) zu empfangen.
  13. Das Lieferungssystem nach Anspruch 12, wobei die besagte Hydrogelrezeptur mindestens einen biologisch aktiven Agenten aufweist.
  14. Das Lieferungssystem nach Anspruch 13, wobei der besagte biologisch aktive Agent aus einer Gruppe, bestehend aus einem lutisierenden Hormon ausgewählt wird, welches ein Hormon (LHRH), LHRH Analoga, Vasopressin, Desmopressin, Corticotropin (ACTH), ACTH Analoga, Calcitonin, Nebenschilddrüsenhormone (PTH), Vasopressin, Desamino [Val4, D-Arg8] arginines Vasopressin, Interferon Alpha, Interferon Beta, Interferon Gamma, Erythropoietin (EPO) Granulozyten-Makrophagen-Kolonie stimulierenden Faktor (GM-CSF), Granulotzyten-Makrophagen-Kolonie stimulierenden Faktor (G-CSF), Interluekin-10 (IL-10), Glukagon, Wachstumshormon, welches (GHRH) freisetzt, Wachstumshormonfreisetzungsfaktor (GHRF), Insulin, Insultropin, Calcitonin, Octreotide, Endorphin, TRN, N-[[(s)-4-oxo-2-Azetidinyl]Carbonyl]-L-Histidyl-L-Prolimanid, Liprezin, Hirnhangsdrüsenhormone, Follikel Luteoide , ANF, Wachstumsfaktoren, MSH, GH, Somatotastin, Bradykinin, Somatotropin, Thrombozytenabgeleiteter Wachstumsfaktor Freisetzungsfaktor, Asparaginase, Bleomycinsulfate, Chymopapain, Cholecystokinin, chorionisches Gonadotropin, Corticotrophin (ACTH), Erythropoietin, Eproprostenol (Thrombozytenaggregationshemmer), Glukagon, HCG, Hirulog, Hyaluronidase, Interferon, Interleukine, Menotropine (Urofollitropin (FSH) und LH), Oxytocin, Streptokinase, Gewebe-Plasminogen-Aktivator, Urokinase, Vasopressin, Desmopressin, ANP, ANP-Freiraum Hemmer, Angiotensin 11 Antagonisten, antidiuretische Hormonagonisten, Bradykinnantagaonisten, Ceredase, CSI's, Calcitoningen bezogene Hormonpeptide (CGRP), Enkephaline, FAB Fragmente, IgE Peptitsuppressoren, IGF-1, Neurotropische Faktoren, Koloniestimulierende Faktoren, Parathyroidhormone (PTH) und Agonisten, Parathyroid Hormonantagonisten, Prostaglandinantagonisten, Pentigetide, Protein C, Protein S, Renin-Inhibitoren, Thymosin Alpha-1, Thrombolytika, TNF, Vasopressinantagonistische Analogika, Alpha-1 Antirypsin (rekombinanten), TGF-beta, Fondaparinux, Ardeparin, Dalteparin, Defibrotide, Enoxaparin, Hirduin, Nadroparin, Reviparin, Tinzaparin, Pentosan-Polysulfate, Oligonukleotide und oligonukleotide Derivate, Alendronsäure, Clodronsäure, Etidronsäure, Ibandronsäure, Incadronsäure Pamidronsäure, Risedronsäure, Tiludronsäure, Zoledronsäure, Argatroban, RWJ 445 167, RWJ 671 818 und Mischungen davon freigibt.
  15. Das Lieferungssystem nach Anspruch 13, wobei der besagte biologisch aktive Agent aus einer Gruppe, bestehend aus Antigenen in der Form von Proteinen, Polysacchariden, Oligosacchariden, Lipoproteinen, geschwächten oder abgetöteten Viren wie Cytomegalovirus, Hepatitis-B-Virus, Hepatitis-C-Virus, dem menschlichen Papillomvirus, Rötelvirus, und Varziella-Zoster, geschwächten oder abgetöteten Bakterien, wie Bordetella Pertussis, Clostridium Tetani, Corynebakterium Diptheriae, A-Gruppen Streptokokken, Legionellenwachstums, Neisseria Meningitide, Pseudomonas Aeruginosa, Streptococcus Pneumoniae, Treponema Pallidum und Vibrio cholerae und Mischungen davon ausgewählt wird.
  16. Das Lieferungssystem nach Anspruch 12, wobei die besagte Hydrogelrezeptur mindestens einen Durchgangspfadmodulator enthält.
  17. Das Lieferungssystem nach Anspruch 12, wobei die besagte Hydrogelrezeptur mindestens einen Vasokonstriktor enthält.
EP04796104A 2003-10-31 2004-10-21 Selbstbetätigter applikator für eine mikroprojektionsanordnung Expired - Lifetime EP1680154B1 (de)

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WO2005044333A3 (en) 2006-06-01
US7097631B2 (en) 2006-08-29
EP1680154A2 (de) 2006-07-19
AR046696A1 (es) 2005-12-21
BRPI0415629A (pt) 2006-12-12
TW200633675A (en) 2006-10-01
KR20060099523A (ko) 2006-09-19
ES2377647T3 (es) 2012-03-29
AU2004287414A1 (en) 2005-05-19
CN100571643C (zh) 2009-12-23
AU2004287414B2 (en) 2010-11-25
JP4682144B2 (ja) 2011-05-11
US20070027427A1 (en) 2007-02-01
EP1680154A4 (de) 2007-07-18
WO2005044333A2 (en) 2005-05-19
ATE539687T1 (de) 2012-01-15
US20050096586A1 (en) 2005-05-05
JP2007509706A (ja) 2007-04-19
CA2543641A1 (en) 2005-05-19
US9421351B2 (en) 2016-08-23

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